Chronic Hepatitis B is a severe infectious disease caused by hepatitis B virus (HBV), widely prevalent throughout the world, and is closely associated with the occurrence of hepatocirrhosis and liver cancer. China belongs to a high prevalence area of Hepatitis B. The results of nationally seropidemiological survey of viral hepatitis in China from 1992 to 1995 showed that the persons carrying viral hepatitis B surface antigen (HBsAg) in China accounted for 9.7% of the population, and it was estimated that there are 1.3×108 HBV carriers. The study on the epidemic situation of viral hepatitis in China showed that the annual reported incidence of hepatitis B as increased from 21.9/100 thousands in 1990 to 53.3/100 thousands in 2003, which exhibited an obvious ascending trendency (see, Wang Xiaojun, Zhang Rongzhen and Hu Yuansheng et al, Disease Monitoring, 2004, 19(8): 290-292). Chronic Hepatitis B not only seriously affects the human health but also imposes heavy economic burden on family and society. Chronic Hepatitis B has become one of the significant public health problems in China.
There are main two classes of drugs useful for the treatment of Chronic Hepatitis B, i.e. immunomodulators and nucleoside DNA polymerase inhibitors (Loomba R., Liang T. J., Antivir. Ther., 2006, 11(1): 1-15), wherein the former includes interferon-α2b (IFN-α2b, Intron A®), and pegylated interferon-α2a (peg-IFN-α2a, Pegasys®); and the latter includes Lamivudine (EPivir-HBV®), Adefovir Dipivoxil (Hepsera®) and Entecavir (Baraclude®). Comparatively speaking, there are limited drugs for the clinical treatment of Hepatitis B in the terms of its number and class. Therefore, it is of significance to continuously research and develop of novel, safe and effective antiviral drugs, in particular those having a totally new mechanism of action.
Deres et al reported the dihydropyrimidine (HAP) compounds substituted by a heteroaryl ring with Bay41-4109 and Bay36-5493 as representatives, which compounds can inhibit HBV replication by blocking the normal formation of nucleocapsids. The pre-clinical data showed that Bay41-4109 has good drug pharmacokinetic parameters (Deres K., Schroder C. H., Paessens A., et al, Science, 2003, 299 (5608): 893-896). The study on their mechanism of action showed that HAP changed the included angle between the dimers for forming the nucleocapsid by interacting with amino residues 113-143 of the core protein, resulting in formation of an unstable and expanded nucleocapsid to accelerate the degradation of the core protein (Hacker H. J., Deres K., Mildenberger M., et al., Biochem. Pharmacol., 2003, 66(12): 2273-2279).